These studies focus on the interactions of inflammatory cells with biomedical materials and target the currently unknown role(s) of lymphocytes in modulating recognized critical activities of adherent macrophages and foreign body giant cells (FBGCs) at the host/biomaterial interface. Our working hypothesis is that biomaterial surface chemistry controls the outcomes of macrophage interactions with lymphocytes, including lymphocyte responses, macrophage behavior, and lymphokine-induced FBGC formation on biomaterials. These innovative studies, which exploit well-characterized model surface- modified materials to elucidate specific roles of lymphocytes and lymphokines in the foreign body response to implanted biomaterials in vivo and in vitro, feature four strategically integrated specific aims that address (1) lymphocyte effects on biomaterial-adherent macrophage behavior, (2) biomaterial-adherent macrophage and FBGC modulation of lymphocyte behavior, (3) mechanisms of biomaterial-dependent lymphokine- induced FBGC formation, and (4) the physiological significance of lymphokine-induced FBGC formation on implanted biomaterials toward defining a biomaterials-induced macrophage activation phenotype. Our established and well-characterized in vitro human monocyte/macrophage and FBGC culture system has been extended to include co-cultures with autologous human lymphocytes. In vitro discoveries will be validated in the in vivo environment with our established mouse cage and subcutaneous implant systems. Our analyses will exploit state-of the-art methods, including proliferation assays, enzyme-linked immunosorbent assays (ELISA), flow cytometry with fluorescence-activated cell sorting (FACS), fluorescence confocal laser scanning microscopy, and immunohistochemistry. Significantly, the combined results from these studies will provide new and crucial perspectives of complex inflammatory cell/biomaterial interactions and will thereby foster novel design and/or management criteria for future biomedical implant materials and tissue-engineered surfaces. PUBLIC HEALTH RELEVANCE: Lymphocyte interactions with macrophages and foreign body giant cells (FBGC) play a far greater role in the inflammatory response to implanted materials than previously appreciated. This investigation is designed to illuminate the significant and incompletely understood relationships between inflammatory cell behaviors on biomaterials and host response mechanisms. Target areas of focus are direct and indirect effects of lymphocytes on critical macrophage/FBGC behaviors, macrophage/FBGC modulation of lymphocyte behaviors, mechanisms of lymphokine-induced macrophage fusion, and the physiological significance of lymphokine-induced FBGC formation. New knowledge from these studies will provide greater perspectives on host responses to implanted biomedical devices, prostheses, and tissue- engineered materials.